S. Chand, P. Karuso / Tetrahedron Letters 58 (2017) 1020–1023
1021
Scheme 1. Synthesis of permethylated scutinin A (1b) and scutinin B (2b) and
conversion back to the natural products (1a, 2a).
Fig. 2. CD spectra of scutinin A hexamethyl ether (1b) (solid) and synthetic sorbityl
hexakis(p-methoxybenzoate) (dashed) recorded in acetonitrile.
was coupled to an oxygenate methylene (4.47/4.36 ppm) and
another methylene (1.58 ppm), which was in turn coupled to the
second methyl (1.05 ppm); a 2-ethylhexane skeleton substituted
at C-1 and C-3 with the two methoxybenzoate groups. This was
confirmed by the total synthesis of racemic 2b from butyraldehyde
Fig. 1. Structures of scutionin A (1a) and scutinin B (2a) and related natural
products.
(
Scheme 2). Briefly, 2-ethylhexane-1,3-diol was synthesised
Table 1
according to the autocondensation method of Pochini and co-
workers. Acylation of the diol with p-anisoyl chloride afforded
synthetic 2b as a mixture of diastereoisomers. The H NMR spectral
data derived from this material was similar to the natural product
(Fig. S3; ESI).
Demethylation of 2b derived from S. antipodes yielded the
natural product scutinin B (2a), which showed a negative Cotton
effect at 250 nm in its CD spectrum (Fig. 3A). Enantioselective
HPLC (Fig. S3B; ESI) of synthetic 2a showed 4 peaks of equal inten-
sity, as expected. Surprisingly, natural 2a showed two peaks in a
Selected NMR data for scutinin A hexamethyl ether (1b).
12
1
Proton
Chemical shift
ppm)
Coupling
constants (Hz)
Coupling constants for
D
-sorbitol hexaacetate1
0
(
H-6proR
H-6proS
H-5
H-4
H-3
H-2
H-1proR
H-1proS
4.68
4.77
5.77
6.18
6.21
5.77
4.41
4.79
12.7, 6.6
12.7, 3.6
12.4 5.3
12.4, 3.7
m
6.7, 4.1
6.3, 4.1
m
1
1
a
m
7.6, 3.4
7.7, 5.3
a
m
12.1, 5.3
12.1, 7.3
12.1, 4.0
12.1, 6.1
2
:3 ratio (Fig. S4C; ESI), indicating a non-equal mixture of two
a
diastereomers. Separation of the 4 isomers by enantioselective
HPLC (Fig. S4B; ESI) showed that the two natural diastereomers
Multiplet from which coupling constants could not be extracted.
(
Fig. S4D; ESI) both had a negative Cotton effects at ꢀ250 nm
(Fig. 3B; peaks 2 and 4).
Peracylation of D-sorbitol and D-mannitol with p-anisoyl chlo-
To determine the absolute stereochemistry of 2a, the CD spectra
were compared to those which were available in the literature.
However, there is very little data for acyclic 1,3-diols, except as
ride afforded sorbityl hexakis(p-methoxybenzoate) (1b) and man-
nityl hexakis(p-methoxybenzoate) (see ESI), respectively. Analysis
of the spectroscopic data derived from each of the synthetic ana-
metal complexes, so this was of limited use. Similarly, the benzoate
logues revealed that the hexaester of
D
-sorbitol showed identical
13,14
sector rule,
which was also established for cyclic secondary
1
H NMR (Fig. S2; ESI), IR and circular dichroism (CD) spectra
Fig. 2) to compound (1b). Compound 1b was converted back to
15
alcohols was not useful. Application of Brewster’s method sug-
gested that the 2a was a mixture of (2R,3R) and (2S,3R), both of
which would give negative rotations, however, this method of
(
the natural product (1a) using tert-butyl mercaptan and alu-
minium chloride (Scheme 1)11 (see ESI).
Compound 2b, obtained as a colourless oil (6.4 mg, 0.001%), dis-
1
played a molecular ion at m/z 414 in the EI-MS spectrum. The
H
1
3
and C NMR spectral data revealed the presence of two nearly-
equivalent para-disubstituted benzene rings. In the mass spec-
+
+
trum, fragment ions at m/z 152 [C
were observed, which, along with UV spectroscopic data (kmax
58 nm, log 1.75) confirmed the presence of two p-methoxyben-
8 7 3 8 7 2
H O + H] , and 135 [C H O ]
2
e
1
zoate moieties. The remaining protons (16H) in the H NMR spec-
trum arise from two methyls, four methylenes and two methines
as established by a C APT experiment. These assignments sug-
gested a molecular formula of C24 for 2b. Analysis of the
1
3
30 6
H O
COSY spectrum showed that there was just one aliphatic spin sys-
tem consisting of a methyl triplet (0.93 ppm), which was coupled
to a methylene (1.39 ppm), which was in turn coupled to another
methylene (1.75 ppm), which was coupled to a methine on oxygen
Scheme 2. Synthesis of racemic scutinin B (2a) (Reagents and conditions: (a) Mg,
EtBr (1.6 equiv), Et
0 min; (b) butyraldehyde (1.0 equiv), HMPA, 45 °C, 3.5 h, 70%; (c) KOH (12 equiv),
aqueous ethanol (1:20), reflux, 3 h, 97%; (d) p-anisoyl chloride (4.1 equiv), pyridine
4.1 equiv), DMAP (cat.), CHCl , rt, 5 h, 56%; (e) AlCl (1.8 equiv), t-buylthiol (1.8
equiv), CH Cl , 0 °C then 2b (1.0 equiv), rt, 12 h, 89%).
2 2
O, rt, 1 h; then phenol (1.0 equiv), Et O, reflux, 1 h, then 90 °C,
3
(
3
3
(
5.35 ppm), coupled to another methine (2.09 ppm). This methine
2
2